The regulation of the cell cycle is mainly influenced by a family of serine/threonine kinases, such serine/threonine kinases are also known as cyclin-dependent kinases (CDKs). They promote the progression of the cell cycle, the transcription of the genetic information, and the normal division and proliferation of cells by binding to the corresponding cyclins which regulate the subunits. CDK4/6 is the critical regulatory factor of the cell cycle and is capable of triggering the transition of the cell cycle from the growth phase (G1 phase) to the DNA replication phase (S1 phase). During the cell proliferation, the complex formed by cyclin D and CDK4/6 can phosphorylate the retinoblastoma protein (Rb). Upon the phosphorylation of the tumor suppressor protein Rb, the transcription factor E2F which has been tightly bound to the unphosphorylated Rb can be released. The activation of E2F further transcribe, which promotes the cell cycle to pass the restriction point (R point) and proceed from the G1 phase to the S phase, leading to the cycle of cell proliferation. Hence, inhibiting CDK4/6 from forming Cyclin D-CDK4/6 complex can prevent the progression of the cell cycle from G1 phase to S phase and thereby realizing the purpose of inhibiting the tumor proliferation. In estrogen receptor positive (ER+) breast cancer (BC), overactivity of CDK4/6 is rather frequent while CDK4/6 is a critical downstream target of the estrogen receptor (ER) signaling. Preclinical data suggests that the dual inhibition of CDK4/6 and the ER signaling produces a synergistic effect and is capable of inhibiting the growth of estrogen receptor positive (ER+) breast cancer (BC) cells in the G1 phase.
CDK4/6 as a target has been a development area with fierce competition. In 2010, Pietzsch summarized the development in this field (Mini-Rev. Med. Chem. 2010, 10, 527-539). In 2014, Malorni also summarized the latest achievements of CDK4/6 inhibitors in the preclinical and clinical research on breast cancer (Curr. Opin. Oncol. 2014, 26, 568-575). Extensive research on CDK4/6 promoted the development of a series of CDK inhibitors with different selectivity and also led to the discovery of a few CDK4/6 inhibitors with efficacy and high selectivity. Palbociclib (PD0332991) is one of these CDK4/6 inhibitors with efficacy and high selectivity, it has entered the human clinical trials and has been applied to the treatment of women with estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer. On the basis of the mid-term data of PALOMA-1, Pfizer has filed a New Drug Application (NDA) of palbociclib to the United States Food and Drug Administration (FDA) in August 2014. In February 2015, the FDA approved the request of launching palbociclib. Abemaciclib (LY2835219) and LEE-011, two other CDK4/6 inhibitors, have begun to recruit patients for their phase 3 clinical trials. These small-molecule heterocyclic compounds are applicable for the treatment of a variety of other cancers in addition to breast cancer. These patents include WO2012018540, WO2012129344, WO2011101409, WO2011130232, WO2010075074, WO2009126584, WO2008032157 and WO2003062236.

We hope to develop a new generation of CDK4/6 inhibitors with high selectivity, higher safety and higher efficacy to better meet the market's demands and achieve better therapeutic efficacy of tumor. The present invention provides a selective CDK4/6 inhibitor with a novel structure, and the compounds with the structure are found to show excellent anticancer effect.